A challenging and long-standing problem has been to find ways of transporting drugs across the blood-brain barrier (BBB)—a barrier that is composed of tightly packed endothelial cells that separates circulating blood from cerebrospinal fluid (CSF) in the central nervous system (CNS). Thus, many drugs that have the potential for treating diseases of the brain are ineffective due to their limited ability to cross this barrier. Most drugs that can cross the BBB do so by passive transport—a process that usually favors small lipophilic molecules. One example of a drug whose efficacy in the CNS is limited due to poor BBB-transport is Amphotericin B (AmphB). AmphB remains the most potent fungicidal drug for the treatment of cryptococcal meningitis after over 50 years of studies in man and other animals. This success occurs despite extremely low levels of AmphB entering the cerebrospinal fluid where over a million yeast cells may reside with established cryptococcal infections. The ability to rapidly kill yeast cells in the subarachnoid space has been correlated with improved outcome. While certain lipid formulations of AmphB have improved its therapeutic to toxic ratio, they are still unable to deliver potent levels of AmphB to the subarachnoid space without dose limiting systemic toxicity. Thus, the ability to deliver significantly higher concentrations of AmphB to the subarachnoid space would be a major therapeutic advantage.
To the extent that fungal infections may contribute to other neurologic disease including Alzheimer's disease, any improvement in transport of AmphB across the BBB could have value in treating these diseases as well. Problematically, the doses required to deliver therapeutic amounts across the BBB have rate limiting systemic toxicity. As such, there remains a need for reducing the toxicity of these drugs to mammalian cells while improving selectivity and efficacy against infectious microbial agents and not compromising the ability to cross the BBB. Embodiments of the present invention provide such solutions.